Nucynta

— THERAPEUTIC CATEGORIES —
  • Narcotic analgesics
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Nucynta Generic Name & Formulations

    Legal Class

    CII

    General Description

    Tapentadol 50mg, 75mg, 100mg tabs.

    Pharmacological Class

    Opioid agonist.

    See Also

    How Supplied

    Tabs—100; ER tabs—60

    How Supplied

    Nucynta Tablets are supplied in bottles of 100. All tablets are round and biconvex-shaped, and available in the following strengths and packages:

    • 50 mg tablets are yellow and debossed with “O-M” on one side and “50” on the other side.

    • 75 mg tablets are yellow-orange and debossed with “O-M” on one side and “75” on the other side.

    • 100 mg tablets are orange and debossed with “O-M” on one side and “100” on the other side.

    Storage

    Store at 20º–25°C (68°F–77ºF); excursions permitted to 15º–30ºC (59º–86ºF) [see USP Controlled Room Temperature]. Protect from moisture.

    Keep in a secure place out of reach of children.

    Nucynta tablets that are no longer needed should be destroyed by flushing down the toilet.

    Manufacturer

    Collegium Pharmaceutical, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI).

    Nucynta Indications

    Indications

    Acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

    Limitations of Use

    Use only if alternative treatment options (eg, non-opioid analgesics, opioid combination products) are ineffective, not tolerated, or otherwise inadequate to provide sufficient analgesia.

    Nucynta Dosage and Administration

    Adult

    Use lowest effective dose for shortest duration. ≥18yrs: initially 50–100mg every 4–6 hrs as needed. First day of dosing: may give second dose one hour after first dose if pain relief is inadequate; subsequent doses should be given every 4–6 hrs. Max 700mg/day on the first day, 600mg/day on subsequent days. Moderate hepatic impairment: initially 50mg every 8 hours; max 3 doses/24 hours. Withdraw gradually (esp. if opioid-dependent), taper by ≤10–25% every 2–4 weeks.

    Children

    <6yrs (<40kg): not recommended. Use lowest effective dose for shortest duration. Swallow whole. ≥6yrs (40–59kg): 50mg (max per single dose) every 4hrs, if inadequate, use oral soln; (60–79kg): initially 50mg every 4hrs, may increase to max 75mg per single dose every 4hrs; (≥80kg): initially 50mg every 4hrs, may increase to 75mg every 4hrs or if needed, up to max 100mg per single dose every 4hrs. Max 7.5mg/kg/day. Treatment duration: max 3 days. Hepatic or renal impairment, daily doses >600mg (or >100mg per dose): not recommended.

    Nucynta Contraindications

    Contraindications

    Significant respiratory depression. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. Known or suspected GI obstruction, including paralytic ileus. During or within 14 days of MAOIs.

    Nucynta Boxed Warnings

    Boxed Warning

    Addiction, abuse, and misuse. Risk evaluation and mitigation strategy (REMS). Life-threatening respiratory depression. Accidental ingestion. Neonatal opioid withdrawal syndrome. Risks from concomitant use with benzodiazepines or other CNS depressants.

    Boxed Warning

    Addiction, Abuse, and Misuse 

    • Risk of opioid addiction, abuse, and misuse, that can potentially lead to overdose and death. Prior to initiating treatment, evaluate the risk for each patient and monitor regularly during treatment for the development of any addiction, abuse, and misuse.

    Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

    • REMS is required for these products to ensure that the benefits outweigh the risks of addiction, abuse, and misuse. 

    • Health care providers are strongly encouraged to:

      • Complete a REMS-compliant education program,

      • Counsel patients and/or their caregivers with every prescription, on safe use, serious risks, storage, and disposal,

      • Emphasize the importance of reading the Medication Guide every time it is provided by their pharmacist, and

      • Consider other tools to improve patient, household, and community safety.

    Life-Threatening Respiratory Depression 

    • Monitor for respiratory depression especially during initiation or following a dose increase.

    Accidental Ingestion

    • Accidental ingestion of one dose of Nucynta, especially by children, can result in fatal overdose of tapentadol.

    Neonatal Opioid Withdrawal Syndrome

    • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening.

    • Advise the patient of the risk of neonatal opioid withdrawal syndrome and treat appropriately if opioid use is required for a prolonged period during pregnancy.

    Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

    • Risk of profound sedation, respiratory depression, coma and death with benzodiazepines or other CNS depressants including alcohol.

    • Reserve concomitant use in those for whom alternative options are inadequate; limit dosages/durations to minimum required. Monitor for signs and symptoms of respiratory depression and sedation. 

    Nucynta Warnings/Precautions

    Warnings/Precautions

    Assess the potential need for access to naloxone when initiating and renewing therapy. Consider prescribing naloxone based on risk factors for overdose (eg, history of opioid use disorder, prior opioid overdose, household members or other close contacts at risk for accidental ingestion or overdose). Abuse potential (monitor). Life-threatening respiratory depression; monitor within first 24–72hrs of initiating therapy and following dose increases. Accidental exposure may cause fatal overdose (esp. in children). Sleep-related breathing disorders (including central sleep apnea (CSA), sleep-related hypoxemia); consider dose reduction if CSA develops. COPD, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression; monitor and consider non-opioid analgesics. Hepatic or renal impairment in children: not recommended. Severe renal or hepatic impairment in adults: not recommended. Consider reducing current opioid analgesic dose or rotating opioid if opioid-induced hyperalgesia is suspected. Adrenal insufficiency. Head injury. Increased intracranial pressure, brain tumors; monitor. Seizure disorders. CNS depression. Impaired consciousness, coma, shock; avoid. Biliary tract disease. Acute pancreatitis. Drug abusers. Reevaluate periodically. Avoid abrupt cessation. Elderly. Cachectic. Debilitated. Pregnancy; potential neonatal opioid withdrawal syndrome during prolonged use. Labor & delivery: not recommended. Nursing mothers: monitor infants if used; for ER tabs: not recommended.

    Warnings/Precautions

    Addiction, Abuse and Misuse

    • Prior to initiation, assess the risks for opioid addiction, abuse, and misuse. Monitor regularly for development of these behaviors and conditions during treatment.

    • Increased risk in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression).

    • To reduce these risks, prescribe the smallest appropriate quantity and advise the patient on the proper disposal of unused drug.

    Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) 

    • REMS is required for these products to ensure that the benefits outweigh the risks of addiction, abuse, and misuse. 

    • Health care providers are strongly encouraged to:

      • Complete a REMS-compliant education program,

      • Counsel patients and/or their caregivers with every prescription, on safe use, serious risks, storage, and disposal,

      • Emphasize the importance of reading the Medication Guide every time it is provided by their pharmacist, and

      • Consider other tools to improve patient, household, and community safety.

     Opioid-Induced Hyperalgesia and Allodynia

    • Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.

    • Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.

    • If a patient is suspected to be experiencing OIH, consider decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety).

    Life-Threatening Respiratory Depression 

    • Monitor closely for respiratory depression especially within the first 24-72 hours of initiation or following a dose increase.

    • Accidental ingestion of one dose of Nucynta, especially by children, can result in fatal overdose of tapentadol.

    • Educate patients and caregivers on how to recognize respiratory depression.

    • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Consider dose reduction if CSA develops. 

    • Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose 

      • Assess the potential need for access to naloxone when initiating and renewing therapy. 

      • Consider prescribing naloxone based on risk factors for overdose (eg, history of opioid use disorder, prior opioid overdose, household members or other close contacts at risk for accidental ingestion or overdose).

    Neonatal Opioid Withdrawal Syndrome

    • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening.

    • Advise the patient of the risk of neonatal opioid withdrawal syndrome and treat appropriately if opioid use is required for a prolonged period during pregnancy.

    • Monitor newborns for signs of neonatal opioid withdrawal syndrome.

    Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

    • Risk of profound sedation, respiratory depression, coma and death with benzodiazepines or other CNS depressants including alcohol.

    • Reserve concomitant use in those for whom alternative options are inadequate; limit dosages/durations to minimum required. Monitor for signs and symptoms of respiratory depression and sedation. 

    • If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.

    • Advise patients and caregivers about the risks of respiratory depression and sedation when used with benzodiazepines or other CNS depressants. Do not operate heavy machinery until the effects of concomitant use have been determined.

    • Screen for the risk of substance use disorders.

    Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

    • Contraindicated to use Nucynta in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

    • Patients with Chronic Pulmonary Disease:

      • Increased risk for decreased respiratory drive including apnea in patients with significant COPD or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression.

    • Elderly, Cachectic, or Debilitated Patients: 

      • Increased risk for life-threatening respiratory depression in these patients.

    • Monitor these patients closely especially during initiation and titration of Nucynta, and when given concomitantly with other drugs that depress respiration. Consider using non-opioid analgesics in these patients.

    Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

    • Discontinue Nucynta if serotonin syndrome is suspected.

    • Risk for serotonin syndrome during concomitant use with serotonergic drugs including SSRIs, SNRIs, TCAs, triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, tramadol), certain muscle relaxants (eg, cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors).

    Adrenal Insufficiency

    • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use.

    • If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. 

    • If confirmed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

    Severe Hypotension 

    • Nucynta may cause severe hypotension (eg, orthostatic hypotension, syncope) in ambulatory patients.

    • Increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating Nucynta.

    • Avoid use of Nucynta in patients with circulatory shock because Nucynta may cause vasodilation in these patients that can further reduce cardiac output and blood pressure.

    Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

    • The use of Nucynta in patients with evidence of increased intracranial pressure or brain tumors may result in further increased intracranial pressure. Monitor these patients for signs of sedation and respiratory depression especially during initiation.

    • Avoid use of Nucynta in patients with impaired consciousness or coma.

    Risk of Use in Patients with Gastrointestinal Conditions 

    • Nucynta is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.

    • Nucynta may cause spasms of the sphincter of Oddi and may cause increases in serum amylase. Monitor for worsening symptoms in patients with biliary tract disease, including acute pancreatitis.

    Increased Risk of Seizures in Patients with Seizure Disorders

    • Nucynta may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.

    • Monitor patients with a history of seizure disorders for worsened seizure control during therapy.

    Withdrawal

    • Avoid abrupt cessation in patients physically dependent on opioids. Gradually taper dosage when discontinuing Nucynta in a physically dependent patient. 

    • Rapid tapering of tapentadol in a physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

    • Avoid using with mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Nucynta. 

    Risks of Driving and Operating Machinery

    • Nucynta may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. 

    • Do not drive or operate dangerous machinery unless tolerant to Nucynta.

    Interactions with Alcohol, Other Opioids, and Drugs of Abuse

    • Do not consume alcoholic beverages or use prescription or nonprescription products (eg, alcohol, other opioids, or drugs of abuse while on therapy).

    Risk of Toxicity in Patients with Hepatic Impairment

    • Avoid use in patients with severe hepatic impairment. 

    • Reduce dose in patients with moderate hepatic impairment; monitor closely for respiratory and CNS depression during treatment.

    Risk of Toxicity in Patients with Renal Impairment

    • Not recommended to use in patients with severe renal impairment due to accumulation of a metabolite formed by glucuronidation. 

    • The clinical relevance of the elevated metabolite is not known.

    Pregnancy Considerations

    Risk Summary

    • Prolonged use during pregnancy may cause neonatal opioid withdrawal syndrome.

    • There is insufficient data in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

    Clinical Considerations

    • Fetal/Neonatal Adverse Reactions:

      • Prolonged use during pregnancy may cause respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

      • Monitor newborns for signs/symptoms of opioid withdrawal syndrome and manage accordingly.

    • Labor or Delivery:

      • Not recommended for use in pregnant women during or immediately prior to labor.

      • Opioids cross the placenta and may lead to respiratory depression and psycho-physiologic effects in neonates. Have an opioid antagonist (eg, naloxone) available for reversal of opioid induced respiratory depression in the neonate. 

      • Opioids, including Nucynta, can prolong labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Nucynta tablets and any potential adverse effects on the breastfed infant from Nucynta tablets or from the underlying maternal condition.

    Clinical Considerations

    • Monitor infants exposed to Nucynta through breast milk for excess sedation and respiratory depression. Withdrawal syndromes can occur in breastfed infants.

    Pediatric Considerations

    • Safety and efficacy of Nucynta tablets in pediatric patients <18 years of age have not been established.

    Geriatric Considerations

    • Use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range.

    • Titrate the dosage of Nucynta slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression. It may also be useful to monitor renal function.

    Renal Impairment Considerations

    • Severe renal impairment (CrCl < 30 mL/minute): not recommended.

    • Mild or moderate renal impairment (CrCl 30–90 mL/minute): no dosage adjustment.

    Hepatic Impairment Considerations

    • Severe hepatic impairment (Child-Pugh Score 10 to 15): not recommended.

    • Moderate hepatic impairment (Child-Pugh Score 7 to 9): reduce dose.

    • Mild hepatic impairment (Child-Pugh Score 5 to 6): no dosage adjustment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Infertility: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

    REMS

    YES

    Nucynta Pharmacokinetics

    Absorption

    Mean absolute bioavailability: ~32% (due to extensive first-pass metabolism). Maximum serum concentrations are typically observed at ~1.25 hours after dosing.

    Food Effect:

    • Nucynta may be administered with or without food.
    • When Nucynta was administered after a high-fat, high-calorie breakfast, the AUC and Cmax increased by 25% and 16%, respectively. 

    Distribution

    Widely distributed throughout the body. Volume of distribution: 540 +/- 98 L. Plasma protein bound: ~20%.

    Metabolism

    Major pathway of metabolism is conjugation with glucuronic acid to produce glucuronides. Tapentadol is also metabolized by CYP2C9, CYP2C19, CYP2D6.

    Elimination

    Renal (99%). Half-life: 4 hours. Clearance: 1530 +/- 177 mL/min.

    Nucynta Interactions

    Interactions

    See Contraindications. Increased risk of hypotension, respiratory depression, sedation with benzodiazepines or other CNS depressants (eg, non-benzodiazepine sedatives/hypnotics, anxiolytics, general anesthetics, phenothiazines, tranquilizers, muscle relaxants, antipsychotics, alcohol, other opioids); reserve concomitant use in those for whom alternative options are inadequate; limit dosages/durations to minimum required; monitor closely; consider prescribing naloxone if concomitant use is warranted. Risk of serotonin syndrome with serotonergic drugs (eg, SSRIs, SNRIs, TCAs, triptans, 5-HT3 antagonists, mirtazapine, trazodone, tramadol, cyclobenzaprine, metaxalone, MAOIs, linezolid, IV methylene blue); monitor and discontinue if suspected. Avoid concomitant mixed agonist/antagonist opioids (eg, butorphanol, nalbuphine, pentazocine) or partial agonist (eg, buprenorphine); may reduce effects and/or precipitate withdrawal symptoms. May antagonize diuretics; monitor. Paralytic ileus may occur with anticholinergics.

    Nucynta Adverse Reactions

    Adverse Reactions

    Nausea, constipation, dizziness, vomiting, headache, somnolence; respiratory depression, severe hypotension, syncope, opioid-induced hyperalgesia. Also in children: pruritus, pyrexia.

    Nucynta Clinical Trials

    Clinical Trials

    Orthopedic Surgery – Bunionectomy

    • The efficacy and safety of Nucynta was evaluated in a randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study in patients 18 to 80 years of age who were experiencing moderate to severe pain after unilateral, first metatarsal bunionectomy surgery. Patients received placebo or Nucynta 50mg, 75mg, and 100mg every 4 to 6 hours for 72 hours.

    • At each dose, Nucynta achieved a greater reduction in pain based on SPID48 values compared with placebo. A greater proportion of patients achieved a reduction in pain intensity at 48 hours of 30% or greater, or 50% or greater were significantly higher in patients treated with Nucynta tablets at each dose vs placebo.

    End-Stage Degenerative Joint Disease

    • The efficacy and safety of Nucynta was evaluated in a randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study in patients 18 to 80 years of age who were experiencing moderate to severe pain from end stage degenerative joint disease of the hip or knee. Patients received placebo or Nucynta 50mg and 75mg  every 4 to 6 hours during waking hours for 10 days.

    • At each dose, Nucynta achieved improvement in pain based on the 5-day SPID vs placebo. A greater proportion of patients achieved a reduction in pain intensity at 5 days of 30% or greater, or 50% or greater were significantly higher in patients treated with Nucynta tablets at each dose vs placebo.

    Nucynta Note

    Not Applicable

    Nucynta Patient Counseling

    Patient Counseling

    Storage and Disposal 

    • Advise patients to store Nucynta securely, out of sight and reach of children due to the risks associated with accidental ingestion, misuse, and abuse.

    • Instruct patients to dispose of Nucynta by flushing the unused medication down the toilet if a drug take-back option is not readily available.

    Addiction, Abuse, and Misuse

    • Inform patients of the risk for addiction, abuse, and misuse. Advise patients not to share Nucynta with others.

    Life-Threatening Respiratory Depression 

    • Inform patients of the risk for respiratory depression especially during initiation or dosage increases.

    Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose 

    • Discuss with the patient and caregiver the availability of naloxone when initiating and renewing treatment with Nucynta.

    • If naloxone is prescribed, also advise patients and caregivers: 

      • How to treat with naloxone, in the event of an opioid overdose 

      • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency 

      • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. 

    Interactions with Benzodiazepines or Other CNS Depressants

    • Inform patients to avoid using Nucynta with benzodiazepines or other CNS depressants, including alcohol, due to potentially fatal additive effects.

    Serotonin Syndrome 

    • Advise patients of the signs/symptoms of serotonin syndrome and to seek medical attention immediately if symptoms develop.

    MAO Interaction

    • Do not start MAOIs while taking Nucynta.

    Adrenal Insufficiency

    • Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Seek medical attention if patients experience symptoms of adrenal insufficiency (eg, nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure).

    Hypotension

    • Nucynta may cause orthostatic hypotension and syncope.

    • Instruct patients how to recognize symptoms of low blood pressure and reduce risks for serious consequences by sitting or lying down, or carefully rising from a sitting or lying position.

    Pregnancy Neonatal Opioid Withdrawal Syndrome 

    • Prolonged use of opioids such as Nucynta, during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. 

    Embryo-Fetal Toxicity 

    • Female patients of reproductive potential should be informed that Nucynta can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy. 

    Lactation 

    • Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek medical care immediately if these signs occur.

    Constipation 

    • Severe constipation can occur during treatment. 

    Cost Savings Program

    Nucynta/Nucynta ER Savings Card

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